The main goal of this translational and exploratory application is to investigate the efficacy of tonic inhibition therapy for status epilepticus (SE), a neurological emergency characterized by a prolonged, continuous seizure activity with significant mortality and morbidity. Despite several drugs for SE, many patients exhibit resistance to current first-line drugs. We propose that a new class of drugs that promote tonic inhibition produce rapid and effective termination of refractory SE. This novel therapeutic strategy is based on the emerging molecular mechanisms of neurosteroids and also cellular changes involved in SE. Neurosteroids are steroids synthesized locally within the brain that control seizure susceptibility by acting principally at GABA-A receptors that mediate phasic and tonic inhibition. Tonic inhibition, mediated by ambient GABA acting at extrasynaptic receptors, plays a unique role in controlling seizures by "setting" the baseline excitability. Recent work has shown that SE cause significant decrease in synaptic (benzodiazepine-sensitive) phasic inhibition with minimal changes in extrasynaptic (neurosteroid-sensitive) tonic inhibition. Therefore, enhanced sensitivity at extrasynaptic GABA-A receptors and maximally stimulating efficacy at synaptic receptors makes neurosteroids ideal new drugs for controlling SE. This novel treatment strategy aimed at augmenting tonic inhibition and phasic inhibition systems simultaneously has not been tested extensively. Our preliminary studies in the pilocarpine model of SE, using new drugs that enhance these systems, demonstrate the feasibility of this therapy to stop refractory SE. We hypothesize that neurosteroids and selective drugs that enhances phasic and extrasynaptic tonic GABAergic inhibition effectively terminate SE, and thereby rescue epileptogenesis. We propose to test this hypothesis by accomplishing 2 specific aims: (Aim 1) To determine the efficacy of simultaneous augmentation of synaptic and tonic inhibition by ganaxolone in SE in naive and epileptic animals, and (Aim 2) To determine the efficacy of selective augmentation of extrasynaptic tonic inhibition by gaboxadol in SE in naive and epileptic animals. We will use lithium-pilocarpine model of SE in rats, and will treat at 2 time points: 10-minutes or 60-minutes after seizure onset. Behavioral and EEG seizures will be recorded for 24 hours for assessment of drug efficacy. Acute histological outcome will be assessed at 72 hours, chronic epileptogenesis and histology will be studied >3 months after SE. Significance. The findings from these studies will provide critical "proof-of-efficacy" of tonic inhibition therapy and set the stage for developing new drugs for refractory SE. PUBLIC HEALTH RELEVANCE: Status epilepticus is a life-threatening neurological emergency with significant morbidity and mortality in children and adults, and also in military persons with traumatic brain injury. It affects approximately 200,000 cases a year in the USA, with an estimated mortality of over 25,000 patients yearly. This project translates recent molecular investigations in experimental SE into therapy development using a new class of drugs that promote tonic and phasic inhibition. It is hoped that this study will offer novel drugs to successfully terminate persistent or refractory SE and possibly "curing" epilepsy development after SE.